Abstract
Here, we aimed to prepare and optimize liposomal amphotericin B (AmB) while using the supercritical fluid of carbon dioxide (SCF-CO2) method and investigate the characteristics and pharmacokinetics of the SCF-CO2-processed liposomal AmB. Liposomes containing phospholipids, ascorbic acid (vit C), and cholesterol were prepared by the SCF-CO2 method at an optimized pressure and temperature; conventional liposomes were also prepared using the thin film hydration method and then compared with the SCF-CO2-processed-liposomes. The optimized formulation was evaluated by in vitro hemolysis tests on rat erythrocytes and in vivo pharmacokinetics after intravenous administration to Sprague-Dawley rats and compared with a marketed AmB micellar formulation, Fungizone®, and a liposomal formulation, AmBisome®. The results of the characterization studies demonstrated that the SCF-CO2-processed-liposomes were spherical particles with an average particle size of 137 nm (after homogenization) and drug encapsulation efficiency (EE) was about 90%. After freeze-drying, mean particle size, EE, and zeta potential were not significantly changed. The stability study of the liposomes showed that liposomal AmB that was prepared by the SCF method was stable over time. In vivo pharmacokinetics revealed that the SCF-CO2-processed-liposomes were bioequivalent to AmBisome®; the hemolytic test depicted less hematotoxicity than Fungizone®. Therefore, this method could serve as a potential alternative for preparing liposomal AmB for industrial applications.
Highlights
Amphotericin B (AmB), a polyene antibiotic that is produced from Streptomyces nodosus, is widely used against life-threatening systemic infections by fungi, such as Candida albicans or Aspergillus fumigates, as well as parasites, such as Leishmania donovani [1,2]
It was considered that liposomal AmB that was prepared by the supercritical fluid (SCF)-CO2 process was less hematotoxic than a micellar formulation of AmB, Fungizone®
We developed liposomal AmB that was prepared by the SCF-CO2 method
Summary
Amphotericin B (AmB), a polyene antibiotic that is produced from Streptomyces nodosus, is widely used against life-threatening systemic infections by fungi, such as Candida albicans or Aspergillus fumigates, as well as parasites, such as Leishmania donovani [1,2]. AmB has been clinically used since the early 1960s due to its extremely low rate of resistance ( against systemic candidiasis) [3]. The broadest antifungal spectrum of AmB ensures its preeminence over other antifungal agents for the treatment of systemic fungal infections and visceral leishmaniasis for more than 30 years [4,5]. AmB has a very low solubility (about 1 mg/L in water) and low membrane permeability; it is categorized in class IV in the Biopharmaceutical Classification System [6]. A conventional dosage form of AmB, Fungizone® (Apothecon®, Princeton, NJ, USA), a colloidal dispersion with detergents (sodium deoxycholate and buffer), and being available as an injectable, was supposed to resolve these solubility issues; hemolysis and dose-dependent nephrotoxicity were reported upon prolonged administration [8,9]
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